New Analyses Explore Roles of EGFR Amplification, Mutations in Response to TKIs

New Analyses Explore Roles of EGFR Amplification, Mutations in Response to TKIs

ORLANDO-Who is most
likely to benefit from treatment with
gefitinib (Iressa) and erlotinib (Tarceva)?
The clinical and demographic predictors
are well known: Lung cancer
patients with adenocarcinoma or
bronchioalveolar characteristics, those
of East Asian ethnicity, never smokers,
and women have higher rates of
response to the tyrosine kinase inhibitors
(TKIs).
When it comes to molecular predictors,
however, the investigations arejust getting started. Last year's finding
that patients with mutations in the
epidermal growth factor receptor
(EGFR) were more likely to respond
to gefitinib triggered a spate of new
EGFR molecular studies, many of
which were presented at the 41st annual
meeting of this year's ASCO meeting.
Most of these were retrospective
analyses of tissue samples from patients
treated with the drugs, and they
looked at EGFR mutations and othermarkers, especially EGFR copy number
or amplification, to see whether
they correlated with outcome. Because
some of the study findings were contradictory,
discussants at ASCO could
only agree that it was crucial to learn
more.
"Molecular profiling is essential
both in research and ... ultimately, in
caring for patients with lung cancer,"
commented discussant Thomas
Lynch, MD, director of thoracic oncology
at Massachusetts General Hospital
Cancer Center, Boston, at the
conclusion of numerous presentations
related to EGFR.
INTACT and IDEAL
Two of the larger correlative studies
presented at ASCO looked at tissue
samples from completed clinical trials
to see whether outcomes could be correlated
with mutations or some other
factor related to EGFR. Dr. Lynch and
colleagues analyzed data from the two
INTACT and two IDEAL trials, which
tested gefitinib with chemotherapy in
patients with non-small-cell lung cancer
(abstract 7006). Ming-Sound Tsao,
MD, professor of laboratory medicine
and pathobiology in the Department
of Pathology at Princess Margaret Hospital
in Toronto, led analysis of molecular
data from the National Cancer
Institute of Canada's successful BR.21
trial with erlotinib (abstract 7007).
Mutations were associated with better
outcomes in both the IDEAL and
INTACT studies, Dr. Lynch reported.
In the IDEAL trials' 78 evaluable tissue
samples, the response rate for those
with mutations was 46%, compared
with a rate of 10% among those without
mutations-a highly statistically
significant finding. In the INTACT
trials, with more than 300 evaluable
samples, the response rate was higher
in the group with mutations-72% vs
40%.
Progression-free survival also was
improved among those with mutations
in both trials, reaching statistical
significance in the IDEAL trials. Overall
survival appeared better in bothtrials but again, the difference was not
large enough to be statistically significant.
Amplifications and Response
Dr. Lynch's group also looked at
EGFR gene amplification in association
with outcome. They found that
patients with amplification seemed to
do better but the differences in
response rate-56% vs 50% in the
INTACT trial and 29% vs 15% in
IDEAL-did not reach statistical significance.
In contrast, the BR.21 analysis
showed that EGFR amplification wasa significantly strong predictor of outcome-
more powerful, in fact, than
mutational status. Dr. Tsao and colleagues
found a high gene copy number
was associated with a response rate
of 20% compared to just 2.4% in patients
with a low gene copy number
(P = .03). Though mutations did correlate
with response in BR.21, the differences
were not significant, and no
survival benefit was seen among patients
with mutations.
Another study presented at ASCO
also found EGFR gene amplification
to be a strong predictor of response
(abstract 7030). Fred Hirsch, MD,
from the University of Colorado Cancer
Center, Aurora, and colleagues
analyzed samples from patients with
bronchioalveolar carcinoma, a unique
type of NSCLC that is resistant to chemotherapy.
They found that an increased
gene copy number, as measured
by fluorescent in situ
hybridization or FISH, was predictiveof response and survival to gefitinib.
This study supported a recent finding
from the same group, reported by
Federico Cappuzzo, MD and colleagues
(J Natl Cancer Inst May
4;97(9):643-655, 2005). That study
also found gene copy number, as determined
by FISH, to be a significant
predictor of response and survival to
gefitinib in patients with advanced
NSCLC.
EGFR Amplification:
A Distinct Subgroup?
Both studies showed that EGFR
mutations correlate closely with the
clinical characteristics associated with
better outcome.
Two other, smaller studies yielded
mixed findings regarding mutations
and amplifications. Toshimi Takano,
MD, of the National Cancer Center
Hospital in Tokyo, and colleagues analyzed
surgical specimens from 66 patients
treated with gefitinib (abstract
7032). They found that EGFR mutations
were a major determinant of response
and survival, but also found
that EGFR gene copy number was significantly
associated with mutational
status. Dr. Takano noted that he considers
EGFR copy number "as a surrogate
marker for EGFR mutations rather
than a true determinant of
EGFR-TKI sensitivity."
On the other hand, no relationship
between amplification and response
was found in a study of tissue samples
from 44 patients treated with gefitinib
or erlotinib, presented by Vincent
Miller, MD, of Memorial Sloan-Kettering
Cancer Center, New York (abstract
7031). Amplification in this
study was measured with chromogenic
in situ hybridization, or CISH. This
study's findings supported the importance
of mutational status, however,
in that EGFR mutations were a powerful
predictor.
Discrepant Findings Explored
Speculating on the reasons for the
discrepant findings related to EGFR
mutations, experts suggested severalpossibilities. Pasi Janne, MD, of Dana-
Farber Cancer Institute, Boston, noted
that there was a wide range of response
rates associated with mutations,
from a low of 16% to a high of
83%. This suggests that mutations are
a part, but not all, of the story, he said
and/or that clinical and molecular
contexts could be important as well.
It's also possible that "all mutations
are not equal," Dr. Janne noted,
and that some have a stronger effect
on response. What's more, there maybe differences in the two agents, gefitinib
and erlotinib, that account for
the different findings.
Different findings on the role of
EGFR amplification also need further
study. Manuel Hidalgo, MD, of Sidney
Kimmel Comprehensive Cancer
Center at Johns Hopkins, Baltimore,
noted that the studies' heterogeneous
patient populations and the fact that
these were all retrospective analyses,
with tissue samples selected based on
availability, could contribute to theinconclusive findings. He also said the
methods used to determine gene
copy-FISH, CISH, and others-
might explain differences, as might
different scoring systems and cutoff
points used to define amplification.
Dr. Janne also speculated that the
different methods of determining
EGFR gene amplification could be a
key issue. "I think additional studies
and characterizations of these groups
will be needed," he said.

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